This invention relates to methods and apparatus for transdermal medicament delivery and to improvements therein. More specifically, this invention relates to improved methods and apparatus for active (as opposed to passive) transdermal, ambulatory drug delivery. Yet more particularly, this invention relates to increasing the efficiency of iontophoresis devices and to improved methods of making and using such devices.
Recently, there has been a renewed interest in the technology of iontophoresis. Iontophoresis has been found to be useful in the transdermal administration or introduction of lidocaine hydrochloride, hydrocortisone, acetic acid, flouride, penicillin, dexamethasone sodium phosphate, and many other drugs. Perhaps the widest use of iontophoresis is the diagnosis of cystic fibrosis using pilocarpine nitrate iontophoresis.
In presently known iontophoresis devices, at least two electrodes are used. Both these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin. The "active" electrode is the electrode from which the ionic drug is delivered into the body. The "indifferent" or ground electrode serves to close the electrical circuit through the body. A battery or other current source is coupled to the electrode to provide the electrical force to drive the drug into the body. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the negative electrode will be the active electrode and the positive electrode will be the indifferent electrode. Of course, simultaneous delivery of drugs from both of the electrodes is also possible.
Generally, iontophoresis electrodes include a reservoir of the drug, typically compounded as a salt of the drug, for example a flouride or sulfate. These reservoirs may take the form of preformed gel bodies, such as disclosed in U.S. Pat. No. 4,382,529 issued to Webster, solid adhesive bodies as disclosed in U.S. Pat. No. 4,416,274, issued to Jacobson, or fluid reservoirs as disclosed in U.S. Pat. No. 4,250,878, issued to Jacobsen. Electrical current is typically applied to the fluid reservoir by means of a current distributing member, which may take the form of a metal plate, a foil layer, a conductive screen, or a dispersion of conductive particles within the drug reservoir.
Typically, the current distributing member in iontophoresis electrodes has been constructed of an inert material, such as stainless steel or platinum. However, more recently use of sacrificial current distributing members which are oxidized or reduced themselves during delivery of the drug has been discussed. Use of sacrificial current distributing members can avoid the pH changes and other adverse effects associated with the hydrolysis of water which generally accompanies the use of inert current distributing members. Electrodes with sacrificial current distributing members are disclosed in U.S. Pat. No. 4,744,787, issued to Phipps et al, incorporated herein by reference in its entirety. Such electrodes are also discussed in the above-cited copending application by Untereker et al, also incorporated herein by reference in its entirety.
An alternative approach to avoiding the adverse effects associated with hydrolysis of water at the current distributing member is disclosed in the published PCT Patent Application No. WO 87/04936, published Aug. 27, 1987, by Sanderson et al, corresponding to U.S. Pat. No. 4,722,726. This electrode system is also described in the article "Noninvasive Delivery of a Novel Inotropic Catecholamine: Iontophoretic Versus Intravenous Infusion in Dogs" by Sanderson et al, published in the Journal of Pharmaceutical Sciences, Vol. 76, No. 3, March 1987, pp. 215-218. In this electrode system, an inert current distributing member is used and the electrode is divided into an upper chamber filled with a buffer and a lower chamber containing the ionic drug. The upper chamber is separated from the lower chamber by means of an ion selective membrane. As described, it is apparently intended that the buffer solution in the upper chamber mitigate the effects of hydrolysis of water, and that the ion selective membrane isolate the drug from the contents of the upper chamber.
In electrodes including fluid reservoirs, as disclosed in U.S. Pat. No. 4,250,878 issued Jacobson, delivery of the drug typically takes place through a microporous membrane. Typically, such membranes are permeable based on size, and therefore must be permeable to any ion equal to or smaller than the drug ion intended to be delivered. In U.S. Pat. No. 4,640,689, issued on Feb. 3, 1987 to Sibalis, an iontophoresis electrode including a gel type drug reservoir provided with a semipermeable membrane is disclosed. This reference also suggests the use of an "ion selective retention gel" intermediate the drug reservoir and the semipermeable membrane. The ion to be retained by the gel is not discussed.